tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2026 May 4:2668752.
doi: 10.1080/22221751.2026.2668752. Online ahead of print.
Enhanced Immunogenicity and Dose-Sparing Efficacy of SelfAmplifying RNA Vaccines Against Seasonal Influenza Across Subtypes
Mengting Huang[SUP] 1 2 [/SUP], Yun Quan[SUP] 1 2 [/SUP], Ruyi Chen[SUP] 2 3 [/SUP], Hao Gu[SUP] 4 5 [/SUP], Wenjun Song[SUP] 2 [/SUP], Feng Zhu[SUP] 1 2 [/SUP], Simin Feng[SUP] 2 3 [/SUP], Jinzhong Lin[SUP] 6 4 [/SUP], Jing Lu[SUP] 4 5 [/SUP], Xuechun Li[SUP] 4 5 [/SUP], Wansheng Li[SUP] 1 2 [/SUP], Qianyu Pan[SUP] 2 [/SUP], Hongli Li[SUP] 1 2 [/SUP], Lei Sun[SUP] 1 2 [/SUP], Tao Jiang[SUP] 7 [/SUP], Bihui Zhang[SUP] 2 [/SUP], Xinqian Yin[SUP] 1 2 [/SUP], Dandan Wei[SUP] 2 8 [/SUP], Changrong Yang[SUP] 1 2 [/SUP], Donglan Liu[SUP] 1 2 [/SUP], Zhongfang Wang[SUP] 1 2 [/SUP], Weixin Jia[SUP] 8 [/SUP], Jincun Zhao[SUP] 1 2 [/SUP], Jieshi Yu[SUP] 9 [/SUP], Xiaobo Li[SUP] 2 [/SUP], Xuedong Yu[SUP] 2 [/SUP], Xiaojing Yue[SUP] 2 [/SUP], Chufang Li[SUP] 2 [/SUP], Fan Bu[SUP] 1 2 [/SUP], Zhichao Miao[SUP] 1 2 [/SUP], Qiong Zhang[SUP] 1 2 [/SUP]
Affiliations
Recent clinical data on seasonal influenza mRNA vaccines have demonstrated suboptimal efficacy against the influenza B virus (IBV). We employed sequence optimization strategies that successfully enhanced the antigen expression of hemagglutinin (HA), and developed mRNA vaccine candidates targeting the WHOrecommended strains. When administered at a low dose (0.1 μg), both mono-and trivalent influenza A mRNA vaccines induced robust humoral immunity and conferred complete protection against homologous viral challenge in murine models, outperforming the quadrivalent inactivated vaccine (QIV, 2 μg). In contrast, IBV mRNA vaccines at an equivalent dose failed to elicit detectable antibodies and offered no protection, consistent with prior of suboptimal immunogenicity in human trials. These findings highlight strain-specific immunogenicity constraints inherent to conventional mRNA platforms. To overcome these limitations, we systematically compared three distinct RNA vaccine modalities: (1) nucleoside-modified mRNA, (2) self-amplifying RNA (saRNA), and (3) circular RNA (circRNA). Notably, a single 0.1 µg dose of trivalent saRNA vaccine elicited robust humoral immunity and provided complete protection against IBV challenge, whereas mRNA vaccination achieved only 14% survival. Importantly, long-term antibody monitoring over 20 weeks showed that saRNA at the low 0.1 μg dose maintained high antibody levels, with a markedly more durable response to IBV antigens than other platforms. Moreover, the trivalent mRNA vaccine exhibited a favorable safety profile, with no obvious abnormal body weight changes or serum biochemical abnormalities observed after immunization. Our findings advocate for strain-adaptive platform selection: conventional mRNA for generating rapid, high-magnitude responses against influenza A, and next-generation saRNA vaccine for enhanced dose efficiency, particularly against IBV.
Keywords: dose-sparing; influenza B virus; seasonal influenza; self-amplifying RNA; trivalent vaccine.
. 2026 May 4:2668752.
doi: 10.1080/22221751.2026.2668752. Online ahead of print.
Enhanced Immunogenicity and Dose-Sparing Efficacy of SelfAmplifying RNA Vaccines Against Seasonal Influenza Across Subtypes
Mengting Huang[SUP] 1 2 [/SUP], Yun Quan[SUP] 1 2 [/SUP], Ruyi Chen[SUP] 2 3 [/SUP], Hao Gu[SUP] 4 5 [/SUP], Wenjun Song[SUP] 2 [/SUP], Feng Zhu[SUP] 1 2 [/SUP], Simin Feng[SUP] 2 3 [/SUP], Jinzhong Lin[SUP] 6 4 [/SUP], Jing Lu[SUP] 4 5 [/SUP], Xuechun Li[SUP] 4 5 [/SUP], Wansheng Li[SUP] 1 2 [/SUP], Qianyu Pan[SUP] 2 [/SUP], Hongli Li[SUP] 1 2 [/SUP], Lei Sun[SUP] 1 2 [/SUP], Tao Jiang[SUP] 7 [/SUP], Bihui Zhang[SUP] 2 [/SUP], Xinqian Yin[SUP] 1 2 [/SUP], Dandan Wei[SUP] 2 8 [/SUP], Changrong Yang[SUP] 1 2 [/SUP], Donglan Liu[SUP] 1 2 [/SUP], Zhongfang Wang[SUP] 1 2 [/SUP], Weixin Jia[SUP] 8 [/SUP], Jincun Zhao[SUP] 1 2 [/SUP], Jieshi Yu[SUP] 9 [/SUP], Xiaobo Li[SUP] 2 [/SUP], Xuedong Yu[SUP] 2 [/SUP], Xiaojing Yue[SUP] 2 [/SUP], Chufang Li[SUP] 2 [/SUP], Fan Bu[SUP] 1 2 [/SUP], Zhichao Miao[SUP] 1 2 [/SUP], Qiong Zhang[SUP] 1 2 [/SUP]
Affiliations
- PMID: 42081324
- DOI: 10.1080/22221751.2026.2668752
Recent clinical data on seasonal influenza mRNA vaccines have demonstrated suboptimal efficacy against the influenza B virus (IBV). We employed sequence optimization strategies that successfully enhanced the antigen expression of hemagglutinin (HA), and developed mRNA vaccine candidates targeting the WHOrecommended strains. When administered at a low dose (0.1 μg), both mono-and trivalent influenza A mRNA vaccines induced robust humoral immunity and conferred complete protection against homologous viral challenge in murine models, outperforming the quadrivalent inactivated vaccine (QIV, 2 μg). In contrast, IBV mRNA vaccines at an equivalent dose failed to elicit detectable antibodies and offered no protection, consistent with prior of suboptimal immunogenicity in human trials. These findings highlight strain-specific immunogenicity constraints inherent to conventional mRNA platforms. To overcome these limitations, we systematically compared three distinct RNA vaccine modalities: (1) nucleoside-modified mRNA, (2) self-amplifying RNA (saRNA), and (3) circular RNA (circRNA). Notably, a single 0.1 µg dose of trivalent saRNA vaccine elicited robust humoral immunity and provided complete protection against IBV challenge, whereas mRNA vaccination achieved only 14% survival. Importantly, long-term antibody monitoring over 20 weeks showed that saRNA at the low 0.1 μg dose maintained high antibody levels, with a markedly more durable response to IBV antigens than other platforms. Moreover, the trivalent mRNA vaccine exhibited a favorable safety profile, with no obvious abnormal body weight changes or serum biochemical abnormalities observed after immunization. Our findings advocate for strain-adaptive platform selection: conventional mRNA for generating rapid, high-magnitude responses against influenza A, and next-generation saRNA vaccine for enhanced dose efficiency, particularly against IBV.
Keywords: dose-sparing; influenza B virus; seasonal influenza; self-amplifying RNA; trivalent vaccine.